The central hypotheses of this CHAVI-ID application are that a successful HIV vaccine should elicit protective antibodies (Abs), and that the combination of B cell and CD4+ T ceil responses is critical for the induction and long-term maintenance of vaccine protection. The overall mission of the application is to define immunogens and immunization regimens that induce sustained HIV cross-protective B cell and CD4+ T cell responses in preclinical models and, thereby, guide product development strategies for a preventive human AIDS vaccine. We propose to develop an HIV vaccine based on a deep understanding of the critical attributes of immune responses that provide protection against AIDS viruses, through two focused and highly integrated efforts. Focus #1 will concentrate on B cell and antibody research to guide the development of immunogens that elicit protective HIV antibody responses in appropriate animal models. Focus #2 will concentrate on CD4+ T cell research, taking advantage of key preliminary data to maximize the T cell help offered to B cell responses through immunization, and to harness the direct antiviral activity of CD4+ T cells. We argue that this combined approach will lead to the discovery of novel immunogens and immunization strategies that will generate measurable cross-protective antibody responses. We will then build on such advances iteratively, by improving the most promising constructs and protocols until vaccine protection is achieved. A critical component of our proposal is the strength of our research team in immunology, virology and structural biology. The Director, Dennis Burton, has made major contributions to understanding broad antibody neutralization of HIV and antibody protection in animal models of HIV infection. The Scientific Leadership Group (SLG) members are Rati Ahmed, Michel Nussenzweig, Bruce Walker and Ian Wilson, who have made crucial advances in describing the structure and function of antibodies against HIV and the induction and maintenance of B and T cell immunity to the virus. The team will be sustained by five Scientific Research Support Components (SRSCs), including strong Operations and Management, that have been assembled to maximally accelerate progress toward the designated goals.